The general purpose of this proposal is to assess the effects of exercise training on coronary vascular dysfunction in heart failure, with a long-term objective of determining its efficacy as a viable treatment and identifying the molecular mechanisms involved. The specific aims of this proposal are: 1.) Determine the effect of exercise training on in vivo smooth muscle dependent coronary vascular function after intracoronary exposure to adenosine, sodium nitroprusside, ET-1, and sarafotoxin (an ET-B receptor agonist) in HF; 2) Determine the effect of exercise training on LV remodeling, capillary surface area, density, diameter, and intercapillary distance; 3)Determine the effects of exercise on in vitro smooth muscle dependent coronary vascular function after exposure to adenosine, ET-1, sarafotoxin, and high potassium depolarizing solutions in denuded coronary rings; 4) Determine the effect of exercise training on K+ and Ca2+ currents, and BKCa, IKCal, and L-type Ca2+ channel expression. A swine pressure-overload model of HF will be utilized, as they have several physiological characteristics similar to humans, and animals placed in either exercise trained or sedentary groups, with age-matched sedentary non-banded counterparts. Animals will exercise for 4 mo. and the following methods will be used to assess its effects: 1) echocardiography for left ventricular remodeling and function; 2) in vivo catheterization for intact coronary vascular function; 3) in vitro coronary ring myography to assess function independent of confounding neural or humoral effects; 4) electrophysiology, RT-PCR, and immunoblot to illuminate molecular mechanisms. The combination of these techniques will allow assessment from the level of the organism to its molecular components. Public Health Relevance: Over 5 million people are diagnosed with heart failure (HF), of which an estimated 57,000 die annually. After diagnosis, life expectancy decreases dramatically and 70-80% of patients die within 8 years. Although the beneficial effects of exercise in other disease has been readily demonstrated, its role as a viable therapy in the treatment of HF is less apparent, although recent evidence suggests it improves survival and quality of life. [unreadable] [unreadable] [unreadable]